tbuckley/cabot-search huggingface dataset:
Multimodal machine learning analysis of more than 220,000 tumor profiles to diagnose molecular and morphological subtypes of cancer.
Authors: Jim Abraham, Sergey Klimov, Eghbal Amidi, Amy B. Heimberger, John Marshall, Elisabeth I. Heath, Joseph J. Drabick, Brian Rubin, Rouba Ali-Fehmi, David R. Braxton, George W. Sledge, David Bryant, Curtis Johnston, Hassan Ghani, Matthew James Oberley, David Spetzler
Journal: Journal of Clinical Oncology (2023)

3078 Background: The diagnosis of a malignancy is typically informed by clinical presentation and tumor tissue features including cell morphology, immunohistochemistry, and molecular markers. Additionally, multi-omic approaches (Abraham 2021 Transl Oncol) and deep learning models using digital pathology (da Silva 2021 J Pathol) have augmented expert pathologists and led to improved diagnoses but are often not employed together on the same patient. The opportunity exists for a truly multimodal, multi-omic machine learning classifier that comprehensively assesses all aspects of a tumor from the molecular underpinnings to the morphological and histological phenotypic presentation to provide the most accurate diagnosis while at the same time providing predictive biomarker data from the same specimen. Methods: Whole transcriptome data from 220,246 tumor profiles, large panel and whole exome data from over 170,000 tumor profiles, and digital pathology features from over 50,000 tumors were used to construct a multi lineage classifier. The classifier was trained on 256 Oncotree classifications corresponding to established WHO diagnoses where a tumor of each class has been observed at least 30 times in our dataset. The dataset was split 50% for training and the other 50% for testing, UMAP was employed for dimensionality reduction, and ensemble models were used for making the final calls. The performance of the classifier was evaluated by comparing with traditional pathologist-directed diagnostic workup. Results: Tumor lineage classifiers predicted the correct classifications where the primary site was known with accuracies ranging between 97% and 100% when using the 32 highest level Oncotree categories corresponding to human tissues. Accuracy on the most granular Oncotree categories varied with many between 90 and 95%. When applied to Cancer of Unknown Primary (CUP) cases (n = 3589), an unequivocal Oncotree classification could be obtained over 90% of the time. Conclusions: Combining multi-omic and digital pathology information into a multimodal artificial intelligence platform can provide comprehensive information to pathologists to aid in diagnosis. This tool can be used to meet an unmet clinical need to define the lineage of CUP cases, which when coupled with biomarker data, will provide an opportunity to examine whether this information can be used to improve the outcomes of patient with CUP.
Detection rate and diagnostic accuracy of sentinel-node biopsy in early stage ovarian cancer: A prospective multicentre study (SELLY).
Authors: Camilla Nero, Nicolò Bizzarri, Stefano Di Berardino, Francesca Sillano, Giuseppe Vizzielli, Francesco Cosentino, Virginia Vargiu, Pierandrea De Iaco, Myriam Perrone, Enrico Vizza, Benito Chiofalo, Stefano Uccella, Fabio Ghezzi, Luigi Carlo Turco, Giacomo Corrado, Diana Giannarelli, Tina Pasciuto, Anna Fagotti, Giovanni Scambia
Journal: Journal of Clinical Oncology (2023)

e17579 Background: Comprehensive surgical staging of early epithelial ovarian cancer includes systematic paraaortic and bilateral pelvic lymphadenectomy but its therapeutic role is controversial and it is associated with potential severe morbidity. The feasibility of sentinel lymph-node (SLN) identification in early stage ovarian cancer has been shown only. We did a prospective multicenter study to assess the feasibility, detection rate and diagnostic accuracy of the SLN procedure in predicting the pathological pelvic-node status in patients with early stage ovarian cancer. Methods: This is a phase II single arm study (EUDRACT 2019-001088-58) including patients with presumed stage I-II epithelial ovarian cancer planned for immediate or delayed minimally-invasive comprehensive staging. The ovarian pedicle is injected with 2 mL of a 1.25 mg/mL indocyanine green (ICG) solution. The pelvic and lumbo-aortic retroperitoneum is then accessed and inspected to identify and remove SLNs. Staging is then completed including systematic pelvic and para-aortic lymphadenectomy and an histopathological examination of all nodes is performed. The primary endpoint was estimation of the sensitivity and sensibility of SLN in predicting nodal status. Assuming a sensitivity of 98.5% in predicting positive sentinel lymph nodes at histology, a pathological lymph node prevalence of 14.2%, a precision of estimate (i.e. the maximum marginal error) d=5%, a type I error α = 0.05, a sample size of 141 patients is needed to test the general hypothesis (i.e. to answer whether SLN(s) identified with ICG can accurately predict nodal status at histology of patients with apparently early EOC). Assuming a drop-out rate of 20%, a total of 176 patients will be enrolled in the study. Results: One-hundred and seventy-six patients were included with a drop-out rate of 22%. Sentinel node was identified in 102 patients (detection rate, 58%, [95% CI: 51-65]). There were no clinical differences between patients with successful or unsuccessful mapping. Both the infundibolopelvic ligament and the legamentum ovarii proprium were injected in 29.0% of cases. Twenty-one patients had positive nodes and 71% of them showed successful mapping. Among the latter, a negative sentinel node was identified in 3 patients (Sensitivity 78.6% [95% CI: 57-100]; Specificity 100%; Accuracy 97% [95% CI: 94-100]; PPV 100%; NPV 96,6% [95% CI: 93-100]). Twenty-two (12.5%) intra- and 25 (14.2%) postoperative complications occurred (12 G1; 9 G2; 2 G3, 2 G4). Clinical trial information: EUCTR2019-001088-58 .
Phase 2 trial of intravesical cabazitaxel, gemcitabine, and cisplatin (CGC) for the treatment of non-muscle invasive BCG unresponsive urothelial carcinoma of the bladder.
Authors: Guarionex Joel DeCastro, Christopher B. Anderson, Cory Abate-Shen, Jillian Gray, Justin Ingram, Mark N. Stein, James M. McKiernan
Journal: Journal of Clinical Oncology (2023)

TPS4616 Background: For patients with non-muscle invasive bladder cancer (NMIBC) unresponsive to Bacille Calmette-Guerin (BCG), multi-agent intravesical trials have been limited. The goal of this Phase 2 study is to investigate the efficacy of intravesical chemotherapy consisting of sequential cabazitaxel, gemcitabine, and cisplatin (CGC) in the salvage setting. Phase 1 results reporting on 18 subjects demonstrated adverse events limited to local Grade 1 and 2 toxicities. Partial funding support for the trial was provided by a pharmaceutical company. Methods: This is a Phase 2 trial (NCT02202772) presently enrolling patients with BCG unresponsive NMIBC as defined by the FDA who refuse or are ineligible for radical cystectomy. All patients undergo pre-treatment transurethral resection of bladder tumor (TURBT) and a 6-week regimen of intravesical cisplatin (100mg), gemcitabine (2gm), and cabazitaxel (5mg). Each drug is instilled weekly except for cisplatin, which is given every other week. Complete response is defined as having no evidence of cancer on post-induction biopsy and negative urine cytology at 3 months. Complete responders proceed with monthly and bimonthly maintenance therapy without cisplatin in the first and second years, respectively, for a total of 24 months. Results: To date thirty-one patients have been enrolled (with target accrual of 33), of whom seven are female. One patient withdrew consent before first evaluation cystoscopy. Mean age thus far is 72 years. All patients have previously received at least two prior induction cycles of BCG, and meet FDA criteria for BCG unresponsive disease. All patients have biopsy proven high grade disease at enrollment; 8 (27%) have high grade T1 disease; and 20 (67%) patients have CIS. Conclusions: Salvage options for BCG unresponsive NMIBC are limited. The CGC protocol has been demonstrated to be safe in a previous Phase 1 study, and accrual for this Phase 2 is near completion. Clinical trial information: NCT02202772 .
UriFind assay and association with whole course management of urothelial carcinoma in a large multicentric, prospective China cohort.
Authors: Xu Chen, Zheng Liu, Liqun Zhou, Jinhai Fan, Weimei Ruan, Hong Wang, Qiang Wei, Haige Chen, Tao Xu, Lei Li, Shaogang Wang, Wanlong Tan, Abai Xu, Jianmei Zhong, Xia Li, Zhiwei Chen, Marina Bibikova, Jian-Bing Fan, Jian Huang, Tianxin Lin
Journal: Journal of Clinical Oncology (2023)

e16588 Background: The gold standard to diagnose and monitor urothelial carcinoma is cystoscopy, which is invasive and painful. The currently available non-invasive methods to detect urothelial carcinoma are either of unsatisfying sensitivity or limited specificity in China. Previously, a DNA methylation assay, termed UriFind, was developed, and showed a compelling sensitivity and specificity in a retrospective cohort. This study aimed to further validate its performance in a large multicentric, prospective China cohort. Methods: Patients involved in the whole course of UC management were recruited in this cohort. The cohort contained 931 patients diagnosed with urothelial carcinoma (UC), and 994 controls with benign diseases and 78 healthy participants from 12 hospitals across China. Urine samples were collected before the therapy, and analyzed with quantitative PCR of ONECUT2 and VIM methylation (UriFind), FISH and urinary cytology. Sensitivity, specificity, accuracy, PPV and NPV of these assays were evaluated as compared to the diagnostic gold standard of cystoscopy, histology results or clinical diagnosis. Results: The UC group of the cohort consisted of 683 non-muscle invasive UC (73.4%), 203 muscle invasive UC (21.8%) and 45 unavailable stage (4.8%). The patients of low, high-grade UC and unavailable grade were 244(26.2%), 651(69.9%) and 36 (3.9%), respectively. Overall sensitivity, specificity, accuracy, PPV and NPV of UriFind was 82.3%, 91.2%, 87.3%, 88.1% and 86.7%, respectively. The specificity of healthy participants was 100%. The overall sensitivity and accuracy of UriFind were significantly higher than urine cytology (40% and 55.7%) and FISH (68.2% and 73.6%), while the specificity was similar to cytology (93.9%) and FISH (87.3%). Importantly, UriFind achieved a great improvement of sensitivity in whole course management, including low grade tumor (56.1%), small and single tumor (63.3%), residual tumor after therapy (71.4%) and recurrent tumor (84.3%). Conclusions: The performance of UriFind is well validated with significantly higher sensitivity and accuracy than urine cytology and FISH in UC detection in this cohort with 2003 cases. This assay facilitates whole course management of urothelial carcinoma, which may reduce the burden of cystoscopy and unnecessary second TURBT. Clinical trial information: NCT04314245 .
Validation of AI-based postoperative nomograms for biochemical recurrence in prostate adenocarcinoma.
Authors: JaeHeon Lee, Tae-Yeong Kwak, Joonyoung Cho, Sun Woo Kim, Hyeyoon Chang, Hong Koo Ha
Journal: Journal of Clinical Oncology (2023)

e17104 Background: After radical prostatectomy (RP), a steep increase in PSA level is an early sign of the disease progression in prostate cancer, which is known as biochemical recurrence (BCR). The risk of BCR can be evaluated based on a combination of clinicopathological factors, and the patient’s Gleason score plays a significant role. However, this scoring system may have lower consistency due to interobserver reproducibility in classifying Gleason Patterns (GP) as well as in quantifying the amount of each GP. We developed AI-based nomograms, with the aim of investigating their prognostic efficacy. Methods: In this study, digitized whole-slide images (WSIs) of H&amp;E-stained prostatectomy specimens and clinical follow-up information were obtained from two sources: Pusan National University Hospital (PNUH, n = 967, event = 342) from 2010 to 2021 with the median follow-up being 3.7 years, and The Cancer Genome Atlas (TCGA, n = 352, event = 79) from 2000 to 2013 with the median follow-up 2.6 years. We used the DeepDx Prostate - RP, an AI-based prostate cancer Gleason grading model, to compute a pixel-wise probability map of each GP in WSIs. Then, a weighted sum of the probabilities and GPs was calculated for each pixel. The proposed slide-level score (AI score) was then determined by averaging them across all pixels in WSI, resulting in a value ranging from 3 to 5. Also, patients were divided into five groups using AI score thresholds (3.1, 3.5, 3.9, and 4.1), and five binary variables (AI score group 1-5) were generated, where a value of 1 indicates a patient’s categorization into a group. To evaluate predictability we created new nomograms incorporating AI scores based on existing nomograms: MSKCC and CAPRA-S. Unlike the original nomograms, the proposed nomograms do not include the Grade Group (GG) made by pathologists. Then, we fitted a Cox regression model on one of two datasets using the original and newly formed nomograms, and validated on the other dataset reporting the concordance index (c-index). Confidence intervals for the c-index were generated via the non-parametric bootstrap resampling with 9,999 samples. Results: The table shows the prognostic performance of sets of clinicopathological factors and demonstrates that the proposed AI score improved the predictive power. The nomograms with AI score group 1-5 outperformed the original nomograms, as shown in (d). Conclusions: In conclusion, we developed the AI-based nomograms which can improve the accuracy of predicting the biochemical recurrence in prostate cancer compared to the existing nomograms. [Table: see text]
ARC-20: A phase 1 dose-escalation and dose-expansion study to investigate the safety, tolerability, and pharmacology of HIF-2α inhibitor AB521 monotherapy in patients with clear cell renal cell carcinoma and other solid tumors.
Authors: Toni K. Choueiri, Benjamin Garmezy, Elaine Paterson, Mohammad Ghasemi, Tzuling Cheng, Paul G. Foster, Ralph J. Hauke, Amita Patnaik
Journal: Journal of Clinical Oncology (2023)

TPS4602 Background: Renal cell carcinoma (RCC) is one of the 10 most common neoplasms in the United States. Patients with clear cell RCC (ccRCC) commonly have inactivation of the von Hippel-Lindau tumor suppressor protein, resulting in accumulation of hypoxia-inducible factor alpha (HIFα) subunits (especially HIF-2α) and leading to tumor growth. AB521, an orally bioavailable small molecule inhibitor of HIF-2α, potently inhibits transcription of HIF-2α-dependent genes in cell lines and preclinical species. Single doses of AB521 (3 mg, 10 mg, 30 mg, and 100 mg) and multiple ascending doses of AB521 (15 mg, 30 mg, and 50 mg) have been previously studied in healthy volunteers. ARC-20 is a first-in-patient study to investigate the safety, tolerability, and pharmacology of AB521 monotherapy in patients with solid tumors and evaluate the clinical activity of AB521 in previously treated patients with ccRCC. Methods: ARC-20 (NCT05536141) is a phase 1, multicenter, open-label study. Eligible patients are adults with solid tumors with ≥1 measurable lesion(s) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and an Eastern Cooperative Oncology Group performance status of 0 or 1. ARC-20 has 2 stages, dose escalation and dose expansion. The dose escalation stage uses a standard 3+3 design and includes patients with pathologically confirmed solid tumors and no other available treatment options. Patients will be sequentially assigned to 1 of 4 cohorts evaluating doses of AB521 ranging from 20 to 200 mg/day. Intermediate dose cohorts may be evaluated based on emergent safety or pharmacologic data. The dose expansion stage will evaluate approximately 30 patients with histologically confirmed ccRCC who have received previous treatment for metastasis with an anti-programmed cell death protein 1 (anti-PD-1) therapy and a vascular endothelial growth factor (VEGF)-targeting tyrosine kinase inhibitor (TKI). Patients previously treated with a HIF-2α-targeting therapy are not eligible for dose expansion. Results from the dose-escalation stage will inform the dose and schedule used during dose expansion. Primary endpoints are the incidence of dose-limiting toxicity and adverse events. Secondary endpoints include objective response rate, AB521 plasma concentration, and AB521 pharmacokinetics. Exploratory endpoints include changes in expression of erythropoietin and other HIF-2α driven biomarkers in blood and tumor tissues, along with progression-free survival for ccRCC patients during dose expansion. Clinical trial information: NCT05536141 .
Eligibility of patients with esophageal and gastroesophageal cancer for biology-guided radiotherapy in a retrospective cohort.
Authors: Santiago Olaechea, Tidie Song, Linda Gilmore, Rodney E Infante, Neil B Desai, Tu Dan, Yuanyuan Zhang, Kenneth D. Westover, Robert D. Timmerman, Orhan K. Oz, Puneeth Iyengar, Aurelie Garant
Journal: Journal of Clinical Oncology (2023)

e16100 Background: Biology-guided radiotherapy (BgRT) is a novel radiotherapy modality that uses real-time positron emission tomography (PET) to guide radiotherapy beamlets. The FDA recently cleared BgRT for clinical use for tumors in lung and bone using 18F FDG radiotracer. We sought to identify esophageal cancer (EC) and gastroesophageal junction cancer (GEJC) patients who may be BgRT candidates based on diagnostic FDG PET/CT imaging. Methods: Through IRB-approved extraction of patient medical record data from an institutional repository of prospectively maintained data, we verified a database of EC and GEJC patients diagnosed at a US tertiary care center between 01/01/2006 and 12/31/2013. When insufficient diagnostic clinical information was present, patients were excluded. Patient and tumor qualities were quantified and subjected to parameters of tumor diameter (≥2cm, &lt;5cm) and maximum standardized uptake value (≥6) to observe potential characteristics of a patient population eligible for this novel BgRT mechanism. Results: Thirty patients met tumor size and FDG uptake criteria for BgRT therapy out of an overall patient cohort of 90 patients. A significantly greater proportion of patients within the BgRT-eligible cohort presented with esophageal tumors (83.3%) compared to non-eligible patients (58.3%, P=0.0177). Otherwise, there was no significant variation of patient sex, race, tumor histology, tumor stage, comorbidity score, and pre-treatment weight loss between patients eligible and not eligible for BgRT therapy. Conclusions: After applying current boundaries of tumor size and radiotracer uptake for effective BgRT intervention, we observed broad applicability of the novel treatment modality across EC/ GEJC patients of varying characteristics and tumor qualities. The high eligibility of patients with tumors located within the esophagus supports further investigation of BgRT in their management. [Table: see text]
A pilot study of the combination of entinostat with capecitabine in high-risk breast cancer after neoadjuvant therapy.
Authors: Clare Humphrey, Trish Ann Millard, Christiana Brenin, Ajay Dhakal, Carla Isadora Falkson, Gina R. Petroni, Nolan Wages, Patrick Michael Dillon
Journal: Journal of Clinical Oncology (2023)

e13107 Background: Breast cancer has an unacceptably high recurrence rate when residual disease is found following neo-adjuvant treatment of high-risk disease. Based on clinical data suggesting an adjuvant role for epigenetic modifying agents in breast cancer and preclinical data suggesting synergistic activity of entinostat combined with capecitabine, we conducted a phase I, open label study of these agents in metastatic breast cancer (MBC). Both agents have published doses for use in combination therapy, but the agents had not previously been combined with each other in a human trial. Methods: A multisite phase I dose escalation study was performed at two academic centers. Patients with pretreated, HER2 negative MBC, and measurable disease were enrolled. Dual dose escalation was performed via a Bayesian partial order continual assessment method. Dose levels ranged from entinostat 3mg to 5mg and capecitabine 800mg/m2 to 1000mg/m2. Results: Thirteen patients with MBC and a median of 4 lines of prior therapy were enrolled across four dose level combinations. The most common toxicities were neutropenia, thrombocytopenia, and palmar- plantar erythrodysesthesia, which were expected toxicities. No new safety signals were observed. One dose-limiting toxicity was observed, which did not exceed a pre-specified toxicity rate of 25%. The median treatment duration was 2.37 months. No partial nor complete responses were observed. The study was halted early prior to entering an expansion phase. Conclusions: The tested dosing combinations of entinostat and capecitabine are likely safe in heavily pretreated metastatic breast cancer patients. Entinostat clinical investigation in breast cancer was halted while this study was ongoing. Clinical trial information: NCT03473639 .
Phase I/IIa clinical trial of a small molecule EBNA1 inhibitor, VK-2019, in patients with Epstein Barr virus–positive nasopharyngeal cancer with pharmacokinetic and pharmacodynamic correlative studies.
Authors: A. Dimitrios Dimitrios Colevas, Michelle A. Rudek, Caroline Even, Victor Ho-Fun Lee, Maura L. Gillison, Saad A. Khan, Rong Lu, Elizabeth Winters, Savanna Biedermann, Steven Lai, Troy Messick
Journal: Journal of Clinical Oncology (2023)

6035 Background: Epstein-Barr Virus (EBV) is associated with a diverse collection of malignancies, including nasopharyngeal carcinoma (NPC). One viral-encoded protein, EBNA1, is consistently expressed in all known EBV-associated malignancies and is critical for the replication and maintenance of the EBV genome in latently infected cells. VK-2019 is a first-in-class, orally bioavailable EBNA1 inhibitor that blocks latent replication and proliferation in preclinical studies. Methods: We conducted a Phase I/IIa clinical trial of VK-2019 as a single therapeutic agent in patients with advanced (recurrent or metastatic) NPC. An accelerated titration design allowed dose escalation to proceed rapidly from 60 mg/day to 1800 mg/day. Blood samples for detailed pharmacokinetic analyses were collected after the first and multiple doses. In addition, tumor biopsies were collected from 2 patients at the 1800 mg/day dose level at baseline and during treatment and analyzed for EBV copy number and viral and cellular gene expression. Results: A total of 22 advanced NPC patients were enrolled. VK-2019 was well tolerated with mostly grade 1-3 adverse events being reported. VK-2019 is rapidly absorbed with a biphasic distribution and a terminal T 1/2 of ~12h after single or multiple doses. C max and AUC increases with dose escalation through 920 mg with large variability at 1800mg. Accumulation has been observed with multiple doses up to 460mg. Based on preclinical efficacy models, target exposures are at or above expected activity levels for patients at least on the 920 mg daily dose and above. A partial response ( &gt; 30% decrease in tumor size) was observed for one patient. Preliminary results from biopsies from 2 patients show decreases in EBV copy number and viral gene expression (LMP2 and gp150). We also observed decreases in EBER-positive cells in one patient. Conclusions: In this study, VK-2019 was well tolerated, exhibiting an excellent safety profile and exposure above in vitro efficacy. An MTD has not been yet established. Preliminary results indicate a decrease in EBV copy number and viral gene expression in latently infected tumor cells in some patients. Alternate dose schedules are justified to determine the clinical efficacy of an EBNA1 inhibitor in patients with advanced NPC. Funded by NCI, R01-CA235633 and Cullinan Oncology. Clinical trial information: NCT04925544 .